This is an application for a K08 for Dr. Salahudeen, a Hematology Oncology Fellow at Stanford University School of Medicine. Dr. Salahudeen has commenced his postdoctoral research in cancer biology and wishes to establish himself as a young investigator in oral cancer translational research. The K08 award for oral cancer research will provide Dr. Salahudeen support to achieve the following goals for his career development: 1) To demonstrate the utility of a novel 3-dimensional ?organoid? in vitro oral cancer model 2) To become proficient in the analysis of clinical, immunology, and genomics data to generate new hypotheses, and 3) to experimentally test these hypotheses in the organoid model for further translational studies and clinical investigation. To oversee Dr. Salahudeen?s training, he will be mentored by Dr. Calvin Kuo, an established figure in organoid culture and cancer biology. Dr. Salahudeen will also be co-mentored by Dr. John Sunwoo, an expert in oral cancer and immunology. In addition to his mentors, Dr. Salahudeen has assembled a group of advisors/collaborators who will lend expertise to Dr. Salahudeen?s proposed research on oral cancer biology. Head and neck squamous cell carcinoma (HNSCC), including oral cancer, is the sixth most common cancer, and a leading cause of cancer-related death. However, HNSCC is a heterogeneous disease with many clinical stratifications including Human Papilloma Virus (HPV) positive cancers, the latter of which carries a more favorable prognosis. In contrast, HPV negative patients have a higher rate of recurrent metastatic disease. Furthermore, HNSCC survival rates have not significantly improved in the last decade due to our limited knowledge of disease biology as compared to other solid tumors. To identify new driver mutations and resistance mechanisms in HNSCC, genome-scale sequencing has identified candidate oncogenic loci but these data have not rapidly translated in preclinical studies. A major obstacle in cancer translational research has been the substantial deficiencies of standard in vitro preclinical models. The current art relies on cancer cell lines, patient derived xenografts grown in immunodeficient mice, or transgenic mice bearing common oncogenes or tumor. These models are not optimal for several reasons and there is a need for an in vitro platform that can rapidly validate candidate oncogenic loci. To overcome these limitations, Dr. Salahudeen has developed a novel oral cancer organoid platform to validate candidate oncogenic loci (AIM1), characterize immune evasion (AIM2), and identify synthetic lethal therapies. In summary, the proposed training and research plan will enhance Dr. Salahudeen?s transition to independence as a physician scientist in oral cancer translational research.